US20090221595A1 - Crystalline form of sitagliptin - Google Patents
Crystalline form of sitagliptin Download PDFInfo
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- US20090221595A1 US20090221595A1 US12/313,975 US31397508A US2009221595A1 US 20090221595 A1 US20090221595 A1 US 20090221595A1 US 31397508 A US31397508 A US 31397508A US 2009221595 A1 US2009221595 A1 US 2009221595A1
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- Prior art keywords
- sitagliptin
- process according
- base
- crystalline form
- organic solvent
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- MFFMDFFZMYYVKS-SECBINFHSA-N sitagliptin Chemical compound C([C@H](CC(=O)N1CC=2N(C(=NN=2)C(F)(F)F)CC1)N)C1=CC(F)=C(F)C=C1F MFFMDFFZMYYVKS-SECBINFHSA-N 0.000 title claims abstract description 135
- 229960004034 sitagliptin Drugs 0.000 title claims abstract description 127
- 238000000034 method Methods 0.000 claims abstract description 37
- 230000008569 process Effects 0.000 claims abstract description 32
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 28
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- 239000003960 organic solvent Substances 0.000 claims description 24
- 239000000203 mixture Substances 0.000 claims description 21
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 18
- 239000012296 anti-solvent Substances 0.000 claims description 18
- 238000001035 drying Methods 0.000 claims description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- 238000004519 manufacturing process Methods 0.000 claims description 12
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 10
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 claims description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 7
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 7
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 7
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 7
- 150000007529 inorganic bases Chemical class 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 229960004115 sitagliptin phosphate Drugs 0.000 claims description 6
- 239000007787 solid Substances 0.000 claims description 6
- RTZRUVMEWWPNRR-UHFFFAOYSA-N tert-butyl n-(3-iodo-1h-pyrrolo[2,3-b]pyridin-5-yl)carbamate Chemical group CC(C)(C)OC(=O)NC1=CN=C2NC=C(I)C2=C1 RTZRUVMEWWPNRR-UHFFFAOYSA-N 0.000 claims description 6
- ARXJGSRGQADJSQ-UHFFFAOYSA-N 1-methoxypropan-2-ol Chemical compound COCC(C)O ARXJGSRGQADJSQ-UHFFFAOYSA-N 0.000 claims description 5
- 239000002244 precipitate Substances 0.000 claims description 5
- 239000002002 slurry Substances 0.000 claims description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 claims description 4
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 4
- 229940011051 isopropyl acetate Drugs 0.000 claims description 4
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 4
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 229910021529 ammonia Inorganic materials 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 3
- 238000001704 evaporation Methods 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 238000001556 precipitation Methods 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 229930195734 saturated hydrocarbon Natural products 0.000 claims 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 238000001144 powder X-ray diffraction data Methods 0.000 abstract description 9
- 239000002585 base Substances 0.000 description 102
- 239000000243 solution Substances 0.000 description 28
- 239000000047 product Substances 0.000 description 20
- 238000003828 vacuum filtration Methods 0.000 description 18
- 239000011541 reaction mixture Substances 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 4
- -1 cyclohexane Chemical class 0.000 description 4
- 230000000704 physical effect Effects 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 239000002178 crystalline material Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 2
- RLSFDUAUKXKPCZ-UITAMQMPSA-N (z)-3-amino-1-[3-(trifluoromethyl)-6,8-dihydro-5h-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)but-2-en-1-one Chemical compound C1CN(C(=NN=2)C(F)(F)F)C=2CN1C(=O)\C=C(/N)CC1=CC(F)=C(F)C=C1F RLSFDUAUKXKPCZ-UITAMQMPSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 229940124213 Dipeptidyl peptidase 4 (DPP IV) inhibitor Drugs 0.000 description 1
- 101800000224 Glucagon-like peptide 1 Proteins 0.000 description 1
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- 102100040918 Pro-glucagon Human genes 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 239000012615 aggregate Substances 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- DMRVBCXRFYZCPR-UHFFFAOYSA-L cycloocta-1,5-diene;ruthenium(2+);dichloride Chemical compound Cl[Ru]Cl.C1CC=CCCC=C1 DMRVBCXRFYZCPR-UHFFFAOYSA-L 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 238000000113 differential scanning calorimetry Methods 0.000 description 1
- 239000003603 dipeptidyl peptidase IV inhibitor Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 230000002641 glycemic effect Effects 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229940126904 hypoglycaemic agent Drugs 0.000 description 1
- 230000009878 intermolecular interaction Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 150000004682 monohydrates Chemical group 0.000 description 1
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 238000000634 powder X-ray diffraction Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 238000000371 solid-state nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000011916 stereoselective reduction Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000002411 thermogravimetry Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
Definitions
- the invention encompasses a polymorph of sitagliptin, processes for preparing the polymorph, and pharmaceutical compositions thereof.
- Sitagliptin (3R)-3-amino-1-[9-(trifluoromethyl)-1,4,7,8-tetrazabicyclo[4.3.0]nona-6,8-dien-4-yl]-4-(2,4,5-trifluorophenyl)butan-1-one, has the following chemical structure:
- Sitagliptin phosphate is a glucagon-like peptide 1 metabolism modulator, hypoglycemic agent, and dipeptidyl peptidase IV inhibitor.
- the phosphate form of Sitagliptin is currently marketed in the United States under the tradename JANUVIATM in its monohydrate form. JANUVIATM is indicated to improve glycemic control in patients with type 2 diabetes mellitus.
- PCT application No. WO 2004/085661 describes sitagliptin, in its free base form, as a crystalline material, and further reports that the crystalline material tends to melt in the range of 114.1° to 115.7° C.
- Polymorphism the occurrence of different crystal forms, is a property of some molecules and molecular complexes.
- a single molecule like sitagliptin, may give rise to a variety of crystalline forms having distinct crystal structures and physical properties like melting point, x-ray diffraction pattern, infrared absorption fingerprint, and solid state NMR spectrum.
- One crystalline form may give rise to thermal behavior different from that of another crystalline form. Thermal behavior can be measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (“TGA”), and differential scanning calorimetry (“DSC”), which have been used to distinguish polymorphic forms.
- TGA thermogravimetric analysis
- DSC differential scanning calorimetry
- polymorphs are distinct solids sharing the same molecular formula yet having distinct advantageous physical properties compared to other crystalline forms of the same compound or complex.
- One of the most important physical properties of pharmaceutical compounds is their solubility in aqueous solution, particularly their solubility in the gastric juices of a patient.
- aqueous solution particularly their solubility in the gastric juices of a patient.
- a drug that is unstable to conditions in the patient's stomach or intestine it is often desirable for a drug that is unstable to conditions in the patient's stomach or intestine to dissolve slowly so that it does not accumulate in a deleterious environment.
- Different crystalline forms or polymorphs of the same pharmaceutical compounds can and reportedly do have different aqueous solubilities.
- the present invention encompasses sitagliptin crystalline form characterized by PXRD pattern having any 5 peaks selected from the group consisting of 7.4, 11.5, 16.7, 17.7, 18.9, 24.1, 24.5, 27.0, 28.5 and 28.8 ⁇ 0.2 degrees 2-theta, wherein any combination of peaks selected includes the peak at 7.4 ⁇ 0.2 degrees two theta, and process of preparing the crystalline form.
- FIG. 1 illustrates a powder XRD pattern of Form I of sitagliptin.
- room temperature refers to a temperature of about 20° C. to about 35° C., more preferably about 25° C. to about 35° C., more preferably about 25° C. to about 30° C., and most preferably about 25° C.
- the present invention encompasses a sitagliptin crystalline form, herein defined as Form I, characterized by a PXRD pattern having any 5 peaks selected from the group consisting of 7.4, 11.5, 16.7, 17.7, 18.9, 24.1, 24.5, 27.0, 28.5 and 28.8 ⁇ 0.2 degrees 2-theta, wherein any combination of peaks selected includes the peak at 7.4 ⁇ 0.2 degrees two theta.
- the present invention encompasses sitagliptin crystalline form I, characterized by a powder XRD pattern as depicted in FIG. 1 .
- the present invention encompasses sitagliptin crystalline form I, further characterized by data selected from the group consisting of a powder XRD pattern with peaks at about 7.4, 16.7, 17.7, 28.5 and 28.8 ⁇ 0.2 degrees 2-theta; a powder XRD pattern with peaks at about 7.4, 11.5, 16.7, 17.7 and 18.9 ⁇ 0.2 degrees 2-theta; a powder XRD pattern with peaks at about 7.4, 11.5, 16.7, 28.5 and 28.8 ⁇ 0.2 degrees 2-theta and a powder XRD pattern with peaks at about 7.4, 24.1, 24.5, 27.0, and 28.8 degrees 2-theta.
- the present invention encompasses a process for preparing sitagliptin crystalline form I of the present invention, comprising providing a mixture of sitagliptin salt, water, and an inorganic base, and recovering the sitagliptin crystalline form from the reaction mixture.
- a mixture of sitagliptin salt, water, and an inorganic base Preferably, from about 2 to about 10 ml of water are used per gram of the sitagliptin salt.
- the sitagliptin salt is sitagliptin phosphate.
- Examples for the inorganic base are NaOH, KOH, Na 2 CO 3 , and K 2 CO 3 .
- sitagliptin salt is slurried in water and further combined with ammonia, to create a two phase system.
- the sitagliptin crystalline form is further recovered from the organic phase.
- ammonia is added to the reaction mixture until a pH of about 8 to about 14 is achieved, preferably, about 9 to about 11, and more preferably, about 10.
- the crystalline form may be recovered from the reaction mixture by any conventional method.
- the crystalline form is recovered by washing and filtrating the organic phase.
- the obtained sitagliptin base form I is further dried at elevated temperature, preferably under reduced pressure (for example less than 1 atmosphere, more preferably, about 10 mbar to about 100 mbar, more preferably, about 10 mbar to about 25 mbar).
- the drying is carried out at a temperature between about 40° C. and about 60° C., preferably between about 45° C. and about 55° C., most preferably about 50° C.
- the drying takes place over a period of about 8 hours to about 36 hours, preferably about 10 hours to about 24 hours, most preferably about 12 hours.
- the present invention encompasses another process for preparing Sitagliptin crystalline form I of the present invention, comprising providing a solution of Sitagliptin base with an organic solvent selected from the group consisting of tetrahydrofuran, dioxane, cyclopentyl methyl ether, C 3 -C 6 ester, such as dimethyl carbonate, isopropyl acetate, a C 2 -C 4 alcohol, such as ethanol, isopropanol, and 1-propanol, and combinations thereof; cooling the solution; and recovering the sitagliptin crystalline form I from the reaction mixture.
- an organic solvent selected from the group consisting of tetrahydrofuran, dioxane, cyclopentyl methyl ether, C 3 -C 6 ester, such as dimethyl carbonate, isopropyl acetate, a C 2 -C 4 alcohol, such as ethanol, isopropanol, and 1-propanol, and combinations thereof.
- the organic solvent is used per 1 gram of the sitagliptin base.
- the Sitagliptin base is dissolved in the organic solvent at a temperature of about 50° C. to about 100° C., and, more preferably, about 55° C. to about 90° C.
- the solution may be maintained at this temperature for about 1 hour to about 4 hours, and, more preferably, about 2 hours to about 3 hours.
- the solution is cooled to a temperature of about 0° C. to about 35° C., more preferably, about 20° C. to about 35° C., even more preferably, about 25° C. to about 30° C., and, most preferably, about 25° C.
- the solution is maintained at the temperature for about 8 hours to about 24 hours, preferably, about 10 hours to about 16 hours, and, most preferably, about 12 hours.
- the obtained sitagliptin base form I is further dried at elevated temperature, and, preferably, under reduced pressure (for example less than 1 atmosphere, more preferably, more preferably, about 10 mbar to about 100 mbar, and, most preferably, about 10 mbar to about 25 mbar).
- the drying is carried out at a temperature between about 40° C. and about 60° C., more preferably, between about 45° C. and about 55° C., and, most preferably, about 50° C.
- the drying takes place over a period of about 8 hours to about 36 hours, more preferably, about 10 hours to about 24 hours, and, most preferably, about 12 hours.
- the present invention encompasses another process for preparing Sitagliptin crystalline form I of the present invention, comprising providing a solution of Sitagliptin base with an organic solvent selected from the group consisting of dioxane, methyl ethyl ketone, propylene glycol monomethyl ether, and methyl isobutyl ketone; adding an antisolvent such as C 5 -C 10 hydrocarbons, such as cyclohexane, and n-hexane, or water; and recovering the sitagliptin crystalline form I from the reaction mixture.
- an organic solvent selected from the group consisting of dioxane, methyl ethyl ketone, propylene glycol monomethyl ether, and methyl isobutyl ketone
- an antisolvent such as C 5 -C 10 hydrocarbons, such as cyclohexane, and n-hexane, or water
- recovering the sitagliptin crystalline form I from the reaction mixture Preferably,
- the Sitagliptin base is dissolved in the organic solvent at a temperature of about 50° C. to about 85° C., and, more preferably, about 55° C. to about 75° C.
- the solution is preferably maintained at this temperature for about 1 hour to about 4 hours, more preferably 2 hours to about 3 hours.
- the solution is then cooled to a temperature of about 20° C. to about 35° C., more preferably about 25° C. to about 30° C., most preferably about 25° C.
- the solution is preferably maintained at this temperature for about 8 hours to about 24 hours, preferably about 10 hours to about 16 hours, most preferably about 12 hours.
- the antisolvent may be added in one step.
- the antisolvent may also be added incrementally. For example, in two or more steps, three or more steps, or four or more steps.
- the steps may be separated by about 1 hour to about 36 hours, 3 hours to about 36 hours, about 8 hours to about 30 hours, preferably, about 10 hours to about 24 hours, and, most preferably, about 12 hours.
- the obtained Sitagliptin base form I is further dried at elevated temperature, preferably, under reduced pressure (less than 1 atmosphere, more preferably, about 10 mbar to about 100 mbar, and, most preferably, about 10 mbar to about 25 mbar).
- the drying is carried out at a temperature between about 40° C. and about 60° C., more preferably, between about 45° C. and about 55° C., and, most preferably, about 50° C.
- the drying takes place over a period of about 8 hours to about 36 hours, more preferably, about 10 hours to about 24 hours, and, most preferably, about 12 hours.
- the present invention encompasses another process for preparing Sitagliptin crystalline form I of the present invention, comprising providing a solution of Sitagliptin base with an organic solvent, selected from the group consisting of ethanol, dimethylformamide, methyl ethyl ketone, and methyl isobutyl ketone, and an antisolvent, preferably, selected from the group consisting of C 5 -C 10 hydrocarbons such as n-hexane, and cyclohexane, or water; preferably, evaporating the solvents to induce precipitation; and recovering the Sitagliptin crystalline form I from the reaction mixture.
- an organic solvent selected from the group consisting of ethanol, dimethylformamide, methyl ethyl ketone, and methyl isobutyl ketone
- an antisolvent preferably, selected from the group consisting of C 5 -C 10 hydrocarbons such as n-hexane, and cyclohexane, or water
- the organic solvent are used per gram of the sitagliptin base.
- from about 5 ml to about 100 ml of the antisolvent are used per gram of the sitagliptin base.
- the Sitagliptin base is dissolved in the organic solvent at a temperature of about 50° C. to about 85° C., and, more preferably, about 55° C. to about 75° C.
- the solution is preferably maintained at this temperature for about 1 hour to about 4 hours, and, more preferably, about 2 hours to about 3 hours.
- the solution is then cooled to a temperature of about 20° C. to about 35° C., more preferably, about 25° C. to about 30° C., and, most preferably, about 25° C.
- the solution is preferably maintained at this temperature for about 8 hours to about 24 hours, more preferably, about 10 hours to about 16 hours, and, most preferably, about 12 hours.
- the antisolvent may be added in one step.
- the antisolvent may also be added incrementally. For example, in two or more steps, three or more steps, or four or more steps.
- the steps may be separated by about 1 hour to about 36 hours, 3 hours to about 36 hours, about 8 hours to about 30 hours, preferably about 10 hours to about 24 hours, and, most preferably, about 12 hours.
- the obtained Sitagliptin base form I is further dried at elevated temperature, preferably under reduced pressure (less than 1 atmosphere, more preferably, about 10 mbar to about 100 mbar, and, most preferably, about 10 mbar to about 25 mbar).
- the drying is carried out at a temperature between about 40° C. and about 60° C., more preferably, between about 45° C. and about 55° C., and, most preferably, about 50° C.
- the drying takes place over a period of about 8 hours to about 36 hours, more preferably, about 10 hours to about 24 hours, and, most preferably about 12 hours.
- the present invention encompasses another process for preparing sitagliptin crystalline form I, comprising providing a slurry of Sitagliptin base with ethyl acetate and n-hexane; heating the slurry; and, preferably, drying the recovered sitagliptin base at elevated temperature under reduced pressure (less than 1 atmosphere, more preferably, about 10 mbar to about 100 mbar, and, most preferably, about 10 mbar to about 25 mbar) to obtain Sitagliptin base form I.
- reduced pressure less than 1 atmosphere, more preferably, about 10 mbar to about 100 mbar, and, most preferably, about 10 mbar to about 25 mbar
- the volume ratio of ethyl acetate to n-hexane is about 1:1 to about 1:5, preferably, about 1:2 to about 1:4, and, most preferably, about 1:3.
- the slurry is preferably heated to a temperature of about 50° C. to about reflux for about 30 minutes to about 4 hours, and, more preferably, for about an hour.
- the solution is then cooled to a temperature of about 20° C. to about 35° C., more preferably, about 25° C. to about 30° C., and, most preferably, about 25° C.
- the solution is preferably maintained at this temperature for about 8 hours to about 24 hours, more preferably, about 10 hours to about 16 hours, and, most preferably, about 12 hours, before collecting the Sitagliptin base.
- the obtained sitagliptin base is further dried at elevated temperature, preferably under reduced pressure (for example less than 1 atmosphere, more preferably, about 10 mbar to about 100 mbar, and, most preferably, about 10 mbar to about 25 mbar).
- the drying is carried out at a temperature between about 40° C. and about 60° C., more preferably, between about 45° C. and about 55° C., and, most preferably, about 40° C.
- the drying takes place over a period of about 8 hours to about 36 hours, more preferably, about 10 hours to about 24 hours, and, most preferably, about 12 hours.
- the present invention encompasses another process for preparing Sitagliptin crystalline form I comprising providing a solution of Sitagliptin base in trifluoroethanol and methyl tert butyl ether; maintaining the solution for a sufficient period of time to obtain a precipitate; collecting and drying the precipitate at elevated temperature under reduced pressure to obtain Sitagliptin base form I.
- a solution of Sitagliptin base in trifluoroethanol and methyl tert butyl ether preferably, from about 3 ml to about 10 ml of the methyl tert butyl ether are used per gram of the sitagliptin base.
- from about 0.2 ml to about 0.5 ml of the trifluoroethanol are used per gram of the sitagliptin base.
- the sitagliptin base is prepared by a reduction reaction of (R)-( ⁇ )-1-[(S)-2-Diphenylphosphino)ferrocenyl]ethyl di-tert-butylphosphine using a chiral catalyst in the presence of hydrogen and trifluoroethanol.
- the obtained sitagliptin base is further crystallized directly from the reaction mixture.
- the drying is carried out at elevated temperature, preferably under reduced pressure (for example less than 1 atmosphere, more preferably, about 10 mbar to about 100 mbar, and, most preferably, about 10 mbar to about 25 mbar).
- the drying is carried out at a temperature between about 40° C. and about 60° C., more preferably, between about 45° C. and about 55° C., and, most preferably, about 50° C.
- the drying takes place over a period of about 8 hours to about 36 hours, more preferably, about 10 hours to about 24 hours, and, most preferably, about 12 hours.
- the solution is maintained at about 5° C. to about 50° C., more preferably, at about 15° C. to about 25° C., and, most preferably, at about room temperature for about 4 hours to about 24 hours, and, more preferably, for about 12 hours.
- the invention further provides pharmaceutical formulations comprising a crystalline form I of sitagliptin of the present invention.
- the compositions of the invention include powders, granulates, aggregates and other solid compositions comprising the present invention form of sitagliptin solid crystalline.
- the present invention also provides methods of treating type 2 diabetes mellitus in a patient, preferably a human, by administrating to the patient a pharmaceutical composition comprising sitagliptin phosphate crystalline form as described herein.
- a pharmaceutical composition comprising sitagliptin phosphate crystalline form as described herein.
- the pharmaceutical composition comprises a therapeutically effective amount of sitagliptin phosphate crystalline form.
- X-Ray powder diffraction data was obtained by using methods known in the art using a SCINTAG powder X-Ray diffractometer model X'TRA equipped with a solid-state detector. Copper radiation of 1.5418 ⁇ was used. A round aluminum sample holder with zero background was used. The scanning parameters included: range: 2-40 degrees two-theta; scan mode: continuous scan; step size: 0.05 deg.; and a rate of 5 deg/min. All peak positions are within ⁇ 0.2 degrees two theta.
- STG (sitagliptin) base 100 mg was dissolved in ethanol (0.5 ml) at 68° C. for 3 hours, then cooled to 25° C., and stirred at 25° C. overnight. Then, 0.5 ml of H 2 O was added, and the mixture stirred at 25° C. for over night. Then, 3 ml of H 2 O was added in portions, and stirred at 25° C. overnight. Then, 2 ml of n-Hexane and 3 Ml H 2 O at 25° C. were added, and the mixture was stirred at 25° C. Crystallization did not occur, and, therefore most of solvent was evaporated. The oil was kept at room temperature for a week. Crystallization occurred. The wet product obtained was STG base crystalline form base I. The sample was dried at 50° C. overnight to obtain a STG base crystalline form base I.
- STG base 100 mg was dissolved in propylene glycol monomethyl ether (0.5 ml) at 68° C. for 3 hours, then cooled to 25° C., and stirred at 25° C. overnight. Then 1 ml of cyclohexane at 25° C. was added, and the mixture was stirred at 25° C. overnight. Then 2 ml of cyclohexane at 25° C. was added, and the mixture was stirred at 25° C. for 3 hours. The product was isolated by vacuum filtration. The sample was dried at 50° C. overnight to obtain STG base crystalline form base I.
- STG base 100 mg was dissolved in tetrahydrofuran (0.3 ml) at 73° C. for 2.25 hours (2 hours and 15 minutes), then cooled to 25° C., and stirred at 25° C. overnight. The product was isolated by vacuum filtration to obtain wet STG base form base I. The sample was dried at 50° C. overnight to obtain STG base crystalline form base I.
- STG base 100 mg was dissolved in dimethyl carbonate (0.5 ml) at 73° C. for 2.25 (2 hours and 15 minutes) hours, then cooled to 25° C., and stirred at 25° C. overnight. The product was isolated by vacuum filtration to obtain wet STG base form base I. The sample was dried at 50° C. overnight to obtain STG base crystalline form base I.
- STG base 100 mg was dissolved in dioxane (0.5 ml) at 73° C. for 2.25 (2 hours and 15 minutes) hours, then cooled to 25° C., and stirred at 25° C. overnight. Then, 0.5 ml of n-hexane at 25° C. was added, and the mixture was stirred at 25° C. for 20 minutes. The product was isolated by vacuum filtration to obtain wet STG base form base I. The sample was dried at 50° C. overnight to obtain STG base crystalline form base I.
- STG base 100 mg was dissolved in ethanol (0.1 ml) at 55° C. for 2 hours, then cooled to 25° C., and stirred at 25° C. overnight. The product was isolated by vacuum filtration to obtain wet STG base form base I. The sample was dried at 50° C. overnight to obtain STG base crystalline form base I.
- STG base 100 mg was dissolved in methyl ethyl ketone (0.2 ml) at 55° C. for 2 hours, then cooled to 25° C., and stirred at 25° C. overnight. Then, 2.5 ml of n-hexane at 25° C. were added, and the mixture was stirred at 25° C. overnight. The product was isolated by vacuum filtration to obtain wet STG base form base I (low crystallinity). The sample was dried at 50° C. overnight to obtain STG base crystalline form base I.
- STG base 100 mg was dissolved in propylene glycol monomethyl ether (0.2 ml) at 55° C. for 2 hours, then cooled to 25° C., and stirred at 25° C. overnight. Then, 0.5 ml of n-hexane at 25° C. was added, and the mixture was stirred at 25° C. overnight. The product was isolated by vacuum filtration to obtain wet STG base form base I. The sample was dried at 50° C. overnight to obtain STG base crystalline form base I.
- STG base 100 mg was dissolved in methyl isobutyl ketone (0.2 ml) at 55° C. for 2 hours, then cooled to 25° C., and stirred at 25° C. overnight. Then, 2.5 ml of n-hexane at 25° C. was added, and the mixture was stirred at 25° C. overnight. The product was isolated by vacuum filtration to obtain wet STG base form base I (low crystallinity). The sample was dried at 50° C. overnight to obtain STG base crystalline form base I.
- STG base 100 mg was dissolved in dioxane (0.2 ml) at 55° C. for 2 hours, then cooled to 25° C., and stirred at 25° C. overnight. The product was isolated by vacuum filtration to obtain wet STG base form base I. The sample was dried at 50° C. overnight to obtain STG base crystalline form base I.
- STG base (2.50 g) was slurried in Ethyl acetate: n-hexane 1:3 (75 ml) at reflux for 55 minutes. Then cooled to room temperature and stirred at room temperature for over night.
- the product was isolated by vacuum filtration. The sample was dried at 40° C. over night to obtain a STG base crystalline form base I.
- STG base (ca. 6 g) was concentrated until the percentage of trifluoroethanol was 39%. This solution was dissolved in methyl t-butyl ether (30 ml) at room temperature and stirred at room temperature overnight. The product was isolated by vacuum filtration. The sample was dried at 40° C. over night to obtain a STG base crystalline form base I.
Abstract
Description
- This application claims the benefit of U.S. provisional application Nos. 61/135,005, filed Jul. 15, 2008, 61/134,878, filed Jul. 14, 2008, and 61/004,383, filed Nov. 26, 2007, hereby incorporated by reference in their entirety.
- The invention encompasses a polymorph of sitagliptin, processes for preparing the polymorph, and pharmaceutical compositions thereof.
- Sitagliptin, (3R)-3-amino-1-[9-(trifluoromethyl)-1,4,7,8-tetrazabicyclo[4.3.0]nona-6,8-dien-4-yl]-4-(2,4,5-trifluorophenyl)butan-1-one, has the following chemical structure:
- Sitagliptin phosphate is a glucagon-like peptide 1 metabolism modulator, hypoglycemic agent, and dipeptidyl peptidase IV inhibitor. The phosphate form of Sitagliptin is currently marketed in the United States under the tradename JANUVIA™ in its monohydrate form. JANUVIA™ is indicated to improve glycemic control in patients with type 2 diabetes mellitus.
- The following PCT Publications describe the synthesis of sitagliptin via stereoselective reduction: WO 2004/087650, WO 2004/085661, and WO 2004/085378.
- PCT application No. WO 2004/085661 describes sitagliptin, in its free base form, as a crystalline material, and further reports that the crystalline material tends to melt in the range of 114.1° to 115.7° C.
- Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single molecule, like sitagliptin, may give rise to a variety of crystalline forms having distinct crystal structures and physical properties like melting point, x-ray diffraction pattern, infrared absorption fingerprint, and solid state NMR spectrum. One crystalline form may give rise to thermal behavior different from that of another crystalline form. Thermal behavior can be measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (“TGA”), and differential scanning calorimetry (“DSC”), which have been used to distinguish polymorphic forms.
- The difference in the physical properties of different crystalline forms results from the orientation and intermolecular interactions of adjacent molecules or complexes in the bulk solid. Accordingly, polymorphs are distinct solids sharing the same molecular formula yet having distinct advantageous physical properties compared to other crystalline forms of the same compound or complex.
- One of the most important physical properties of pharmaceutical compounds is their solubility in aqueous solution, particularly their solubility in the gastric juices of a patient. For example, where absorption through the gastrointestinal tract is slow, it is often desirable for a drug that is unstable to conditions in the patient's stomach or intestine to dissolve slowly so that it does not accumulate in a deleterious environment. Different crystalline forms or polymorphs of the same pharmaceutical compounds can and reportedly do have different aqueous solubilities.
- The discovery of new polymorphic forms and solvates of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic. Therefore, there is a need for additional crystalline forms of sitagliptin.
- The present invention encompasses sitagliptin crystalline form characterized by PXRD pattern having any 5 peaks selected from the group consisting of 7.4, 11.5, 16.7, 17.7, 18.9, 24.1, 24.5, 27.0, 28.5 and 28.8±0.2 degrees 2-theta, wherein any combination of peaks selected includes the peak at 7.4±0.2 degrees two theta, and process of preparing the crystalline form.
-
FIG. 1 illustrates a powder XRD pattern of Form I of sitagliptin. - As used herein, the term “room temperature” refers to a temperature of about 20° C. to about 35° C., more preferably about 25° C. to about 35° C., more preferably about 25° C. to about 30° C., and most preferably about 25° C.
- In one embodiment, the present invention encompasses a sitagliptin crystalline form, herein defined as Form I, characterized by a PXRD pattern having any 5 peaks selected from the group consisting of 7.4, 11.5, 16.7, 17.7, 18.9, 24.1, 24.5, 27.0, 28.5 and 28.8±0.2 degrees 2-theta, wherein any combination of peaks selected includes the peak at 7.4±0.2 degrees two theta.
- In another embodiment, the present invention encompasses sitagliptin crystalline form I, characterized by a powder XRD pattern as depicted in
FIG. 1 . - The present invention encompasses sitagliptin crystalline form I, further characterized by data selected from the group consisting of a powder XRD pattern with peaks at about 7.4, 16.7, 17.7, 28.5 and 28.8±0.2 degrees 2-theta; a powder XRD pattern with peaks at about 7.4, 11.5, 16.7, 17.7 and 18.9±0.2 degrees 2-theta; a powder XRD pattern with peaks at about 7.4, 11.5, 16.7, 28.5 and 28.8±0.2 degrees 2-theta and a powder XRD pattern with peaks at about 7.4, 24.1, 24.5, 27.0, and 28.8 degrees 2-theta.
- In another embodiment, the present invention encompasses a process for preparing sitagliptin crystalline form I of the present invention, comprising providing a mixture of sitagliptin salt, water, and an inorganic base, and recovering the sitagliptin crystalline form from the reaction mixture. Preferably, from about 2 to about 10 ml of water are used per gram of the sitagliptin salt. Preferably, the sitagliptin salt is sitagliptin phosphate.
- Examples for the inorganic base are NaOH, KOH, Na2CO3, and K2CO3.
- In one specific embodiment, sitagliptin salt is slurried in water and further combined with ammonia, to create a two phase system. The sitagliptin crystalline form is further recovered from the organic phase.
- Preferably, ammonia is added to the reaction mixture until a pH of about 8 to about 14 is achieved, preferably, about 9 to about 11, and more preferably, about 10.
- The crystalline form may be recovered from the reaction mixture by any conventional method. Preferably, the crystalline form is recovered by washing and filtrating the organic phase. Preferably, the obtained sitagliptin base form I is further dried at elevated temperature, preferably under reduced pressure (for example less than 1 atmosphere, more preferably, about 10 mbar to about 100 mbar, more preferably, about 10 mbar to about 25 mbar). Preferably, the drying is carried out at a temperature between about 40° C. and about 60° C., preferably between about 45° C. and about 55° C., most preferably about 50° C. Preferably the drying takes place over a period of about 8 hours to about 36 hours, preferably about 10 hours to about 24 hours, most preferably about 12 hours.
- In another embodiment, the present invention encompasses another process for preparing Sitagliptin crystalline form I of the present invention, comprising providing a solution of Sitagliptin base with an organic solvent selected from the group consisting of tetrahydrofuran, dioxane, cyclopentyl methyl ether, C3-C6 ester, such as dimethyl carbonate, isopropyl acetate, a C2-C4 alcohol, such as ethanol, isopropanol, and 1-propanol, and combinations thereof; cooling the solution; and recovering the sitagliptin crystalline form I from the reaction mixture.
- Preferably, from about 1 ml to about 20 ml of the organic solvent is used per 1 gram of the sitagliptin base.
- Preferably, the Sitagliptin base is dissolved in the organic solvent at a temperature of about 50° C. to about 100° C., and, more preferably, about 55° C. to about 90° C. Preferably, the solution may be maintained at this temperature for about 1 hour to about 4 hours, and, more preferably, about 2 hours to about 3 hours.
- Preferably, the solution is cooled to a temperature of about 0° C. to about 35° C., more preferably, about 20° C. to about 35° C., even more preferably, about 25° C. to about 30° C., and, most preferably, about 25° C. After cooling, the solution is maintained at the temperature for about 8 hours to about 24 hours, preferably, about 10 hours to about 16 hours, and, most preferably, about 12 hours.
- Preferably, the obtained sitagliptin base form I is further dried at elevated temperature, and, preferably, under reduced pressure (for example less than 1 atmosphere, more preferably, more preferably, about 10 mbar to about 100 mbar, and, most preferably, about 10 mbar to about 25 mbar). Preferably, the drying is carried out at a temperature between about 40° C. and about 60° C., more preferably, between about 45° C. and about 55° C., and, most preferably, about 50° C. Preferably, the drying takes place over a period of about 8 hours to about 36 hours, more preferably, about 10 hours to about 24 hours, and, most preferably, about 12 hours.
- In another embodiment, the present invention encompasses another process for preparing Sitagliptin crystalline form I of the present invention, comprising providing a solution of Sitagliptin base with an organic solvent selected from the group consisting of dioxane, methyl ethyl ketone, propylene glycol monomethyl ether, and methyl isobutyl ketone; adding an antisolvent such as C5-C10 hydrocarbons, such as cyclohexane, and n-hexane, or water; and recovering the sitagliptin crystalline form I from the reaction mixture. Preferably, from about 1.5 ml to about 2.5 ml of the organic solvent are used per gram of the sitagliptin base. Preferably, from about 20 ml to about 30 ml of antisolvent are used per gram of the sitagliptin base.
- Preferably, the Sitagliptin base is dissolved in the organic solvent at a temperature of about 50° C. to about 85° C., and, more preferably, about 55° C. to about 75° C. The solution is preferably maintained at this temperature for about 1 hour to about 4 hours, more preferably 2 hours to about 3 hours.
- Preferably the solution is then cooled to a temperature of about 20° C. to about 35° C., more preferably about 25° C. to about 30° C., most preferably about 25° C. The solution is preferably maintained at this temperature for about 8 hours to about 24 hours, preferably about 10 hours to about 16 hours, most preferably about 12 hours.
- The antisolvent may be added in one step. The antisolvent may also be added incrementally. For example, in two or more steps, three or more steps, or four or more steps. The steps may be separated by about 1 hour to about 36 hours, 3 hours to about 36 hours, about 8 hours to about 30 hours, preferably, about 10 hours to about 24 hours, and, most preferably, about 12 hours.
- Preferably, the obtained Sitagliptin base form I is further dried at elevated temperature, preferably, under reduced pressure (less than 1 atmosphere, more preferably, about 10 mbar to about 100 mbar, and, most preferably, about 10 mbar to about 25 mbar). Preferably, the drying is carried out at a temperature between about 40° C. and about 60° C., more preferably, between about 45° C. and about 55° C., and, most preferably, about 50° C. Preferably the drying takes place over a period of about 8 hours to about 36 hours, more preferably, about 10 hours to about 24 hours, and, most preferably, about 12 hours.
- In another embodiment, the present invention encompasses another process for preparing Sitagliptin crystalline form I of the present invention, comprising providing a solution of Sitagliptin base with an organic solvent, selected from the group consisting of ethanol, dimethylformamide, methyl ethyl ketone, and methyl isobutyl ketone, and an antisolvent, preferably, selected from the group consisting of C5-C10 hydrocarbons such as n-hexane, and cyclohexane, or water; preferably, evaporating the solvents to induce precipitation; and recovering the Sitagliptin crystalline form I from the reaction mixture. Preferably, from about 2 ml to about 8 ml of the organic solvent are used per gram of the sitagliptin base. Preferably, from about 5 ml to about 100 ml of the antisolvent are used per gram of the sitagliptin base.
- Preferably, the Sitagliptin base is dissolved in the organic solvent at a temperature of about 50° C. to about 85° C., and, more preferably, about 55° C. to about 75° C. The solution is preferably maintained at this temperature for about 1 hour to about 4 hours, and, more preferably, about 2 hours to about 3 hours.
- Preferably the solution is then cooled to a temperature of about 20° C. to about 35° C., more preferably, about 25° C. to about 30° C., and, most preferably, about 25° C. The solution is preferably maintained at this temperature for about 8 hours to about 24 hours, more preferably, about 10 hours to about 16 hours, and, most preferably, about 12 hours.
- The antisolvent may be added in one step. The antisolvent may also be added incrementally. For example, in two or more steps, three or more steps, or four or more steps. The steps may be separated by about 1 hour to about 36 hours, 3 hours to about 36 hours, about 8 hours to about 30 hours, preferably about 10 hours to about 24 hours, and, most preferably, about 12 hours.
- Preferably, the obtained Sitagliptin base form I is further dried at elevated temperature, preferably under reduced pressure (less than 1 atmosphere, more preferably, about 10 mbar to about 100 mbar, and, most preferably, about 10 mbar to about 25 mbar). Preferably the drying is carried out at a temperature between about 40° C. and about 60° C., more preferably, between about 45° C. and about 55° C., and, most preferably, about 50° C. Preferably the drying takes place over a period of about 8 hours to about 36 hours, more preferably, about 10 hours to about 24 hours, and, most preferably about 12 hours.
- In another embodiment, the present invention encompasses another process for preparing sitagliptin crystalline form I, comprising providing a slurry of Sitagliptin base with ethyl acetate and n-hexane; heating the slurry; and, preferably, drying the recovered sitagliptin base at elevated temperature under reduced pressure (less than 1 atmosphere, more preferably, about 10 mbar to about 100 mbar, and, most preferably, about 10 mbar to about 25 mbar) to obtain Sitagliptin base form I.
- Preferably the volume ratio of ethyl acetate to n-hexane is about 1:1 to about 1:5, preferably, about 1:2 to about 1:4, and, most preferably, about 1:3.
- The slurry is preferably heated to a temperature of about 50° C. to about reflux for about 30 minutes to about 4 hours, and, more preferably, for about an hour. Preferably the solution is then cooled to a temperature of about 20° C. to about 35° C., more preferably, about 25° C. to about 30° C., and, most preferably, about 25° C. The solution is preferably maintained at this temperature for about 8 hours to about 24 hours, more preferably, about 10 hours to about 16 hours, and, most preferably, about 12 hours, before collecting the Sitagliptin base.
- Preferably, the obtained sitagliptin base is further dried at elevated temperature, preferably under reduced pressure (for example less than 1 atmosphere, more preferably, about 10 mbar to about 100 mbar, and, most preferably, about 10 mbar to about 25 mbar). Preferably, the drying is carried out at a temperature between about 40° C. and about 60° C., more preferably, between about 45° C. and about 55° C., and, most preferably, about 40° C. Preferably the drying takes place over a period of about 8 hours to about 36 hours, more preferably, about 10 hours to about 24 hours, and, most preferably, about 12 hours.
- In another embodiment, the present invention encompasses another process for preparing Sitagliptin crystalline form I comprising providing a solution of Sitagliptin base in trifluoroethanol and methyl tert butyl ether; maintaining the solution for a sufficient period of time to obtain a precipitate; collecting and drying the precipitate at elevated temperature under reduced pressure to obtain Sitagliptin base form I. Preferably, from about 3 ml to about 10 ml of the methyl tert butyl ether are used per gram of the sitagliptin base. Preferably, from about 0.2 ml to about 0.5 ml of the trifluoroethanol are used per gram of the sitagliptin base.
- Preferably, the sitagliptin base is prepared by a reduction reaction of (R)-(−)-1-[(S)-2-Diphenylphosphino)ferrocenyl]ethyl di-tert-butylphosphine using a chiral catalyst in the presence of hydrogen and trifluoroethanol. Preferably, the obtained sitagliptin base is further crystallized directly from the reaction mixture.
- Preferably, the drying is carried out at elevated temperature, preferably under reduced pressure (for example less than 1 atmosphere, more preferably, about 10 mbar to about 100 mbar, and, most preferably, about 10 mbar to about 25 mbar). Preferably, the drying is carried out at a temperature between about 40° C. and about 60° C., more preferably, between about 45° C. and about 55° C., and, most preferably, about 50° C. Preferably the drying takes place over a period of about 8 hours to about 36 hours, more preferably, about 10 hours to about 24 hours, and, most preferably, about 12 hours.
- Preferably, the solution is maintained at about 5° C. to about 50° C., more preferably, at about 15° C. to about 25° C., and, most preferably, at about room temperature for about 4 hours to about 24 hours, and, more preferably, for about 12 hours.
- The invention further provides pharmaceutical formulations comprising a crystalline form I of sitagliptin of the present invention. The compositions of the invention include powders, granulates, aggregates and other solid compositions comprising the present invention form of sitagliptin solid crystalline.
- The present invention also provides methods of treating type 2 diabetes mellitus in a patient, preferably a human, by administrating to the patient a pharmaceutical composition comprising sitagliptin phosphate crystalline form as described herein. Preferably, the pharmaceutical composition comprises a therapeutically effective amount of sitagliptin phosphate crystalline form.
- Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail the preparation of the composition and methods of use of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.
- X-Ray powder diffraction data was obtained by using methods known in the art using a SCINTAG powder X-Ray diffractometer model X'TRA equipped with a solid-state detector. Copper radiation of 1.5418 Å was used. A round aluminum sample holder with zero background was used. The scanning parameters included: range: 2-40 degrees two-theta; scan mode: continuous scan; step size: 0.05 deg.; and a rate of 5 deg/min. All peak positions are within ±0.2 degrees two theta.
- An 8 g (0.016 mol) sample of Sitagliptin phosphate was slurried in 176 ml (22 vol.) distilled water and stirred at room temperature (pH˜5-6). NH3 (26 ml in water; 0.3 mol) was added in portions until pH˜10 was achieved, and the resulting mixture was washed twice with 160 ml (20 vol.) ethyl acetate. The organic phase was dried over Na2SO4 and evaporated until a white solid was formed. The solid was dried in a vacuum oven (10-25 mbar) at 50° C. overnight. Yield—87.3%; purity—97.06%.
- A sample of STG (sitagliptin) base (100 mg) was dissolved in ethanol (0.5 ml) at 68° C. for 3 hours, then cooled to 25° C., and stirred at 25° C. overnight. Then, 0.5 ml of H2O was added, and the mixture stirred at 25° C. for over night. Then, 3 ml of H2O was added in portions, and stirred at 25° C. overnight. Then, 2 ml of n-Hexane and 3 Ml H2O at 25° C. were added, and the mixture was stirred at 25° C. Crystallization did not occur, and, therefore most of solvent was evaporated. The oil was kept at room temperature for a week. Crystallization occurred. The wet product obtained was STG base crystalline form base I. The sample was dried at 50° C. overnight to obtain a STG base crystalline form base I.
- A sample of STG base (100 mg) was dissolved in propylene glycol monomethyl ether (0.5 ml) at 68° C. for 3 hours, then cooled to 25° C., and stirred at 25° C. overnight. Then 1 ml of cyclohexane at 25° C. was added, and the mixture was stirred at 25° C. overnight. Then 2 ml of cyclohexane at 25° C. was added, and the mixture was stirred at 25° C. for 3 hours. The product was isolated by vacuum filtration. The sample was dried at 50° C. overnight to obtain STG base crystalline form base I.
- A sample of STG base (100 mg) was dissolved in dimethyl formamide (0.3 ml) at 68° C. for 3 hours. Then the solution was cooled to 25° C., and stirred at 25° C. overnight. Then cyclohexane and H2O at 25° C. were added, and the mixture was stirred at 25° C. overnight. Then 3 ml of cyclohexane at 25° C. were added, and the mixture was stirred at 25° C. overnight. Then 4 ml of cyclohexane at 25° C. were added, and the mixture was stirred at 25° C. overnight. Most of the solvent was evaporated, and then crystallization occurred. The product was isolated by vacuum filtration to obtain wet STG base crystalline form base I. The sample was dried at 50° C. overnight to obtain STG base crystalline form base I.
- A sample of STG base (100 mg) was dissolved in methyl isobutyl ketone (0.8 ml) at 68° C. for 3 hours, cooled to 25° C., and stirred at 25° C. overnight. Then, 1 ml of cyclohexane at 25° C. was added, and the mixture was stirred at 25° C. overnight. Then, 2 ml of cyclohexane at 25° C. were added, and the mixture was stirred at 25° C. overnight. Then, 5 ml of cyclohexane at 25° C. were added, and the mixture was stirred at 25° C. overnight. The solvent was evaporated from a small amount of product, and the product was isolated by vacuum filtration to obtain wet STG base form base I. The sample was dried at 50° C. overnight to obtain STG base crystalline form base I.
- A sample of STG base (100 mg) was dissolved in tetrahydrofuran (0.3 ml) at 73° C. for 2.25 hours (2 hours and 15 minutes), then cooled to 25° C., and stirred at 25° C. overnight. The product was isolated by vacuum filtration to obtain wet STG base form base I. The sample was dried at 50° C. overnight to obtain STG base crystalline form base I.
- A sample of STG base (100 mg) was dissolved in dimethyl carbonate (0.5 ml) at 73° C. for 2.25 (2 hours and 15 minutes) hours, then cooled to 25° C., and stirred at 25° C. overnight. The product was isolated by vacuum filtration to obtain wet STG base form base I. The sample was dried at 50° C. overnight to obtain STG base crystalline form base I.
- A sample of STG base (100 mg) was dissolved in dioxane (0.5 ml) at 73° C. for 2.25 (2 hours and 15 minutes) hours, then cooled to 25° C., and stirred at 25° C. overnight. Then, 0.5 ml of n-hexane at 25° C. was added, and the mixture was stirred at 25° C. for 20 minutes. The product was isolated by vacuum filtration to obtain wet STG base form base I. The sample was dried at 50° C. overnight to obtain STG base crystalline form base I.
- A sample of STG base (100 mg) was dissolved in ethanol (0.1 ml) at 55° C. for 2 hours, then cooled to 25° C., and stirred at 25° C. overnight. The product was isolated by vacuum filtration to obtain wet STG base form base I. The sample was dried at 50° C. overnight to obtain STG base crystalline form base I.
- A sample of STG base (100 mg) was dissolved in methyl ethyl ketone (0.2 ml) at 55° C. for 2 hours, then cooled to 25° C., and stirred at 25° C. overnight. Then, 2.5 ml of n-hexane at 25° C. were added, and the mixture was stirred at 25° C. overnight. The product was isolated by vacuum filtration to obtain wet STG base form base I (low crystallinity). The sample was dried at 50° C. overnight to obtain STG base crystalline form base I.
- A sample of STG base (100 mg) was dissolved in propylene glycol monomethyl ether (0.2 ml) at 55° C. for 2 hours, then cooled to 25° C., and stirred at 25° C. overnight. Then, 0.5 ml of n-hexane at 25° C. was added, and the mixture was stirred at 25° C. overnight. The product was isolated by vacuum filtration to obtain wet STG base form base I. The sample was dried at 50° C. overnight to obtain STG base crystalline form base I.
- A sample of STG base (100 mg) was dissolved in methyl isobutyl ketone (0.2 ml) at 55° C. for 2 hours, then cooled to 25° C., and stirred at 25° C. overnight. Then, 2.5 ml of n-hexane at 25° C. was added, and the mixture was stirred at 25° C. overnight. The product was isolated by vacuum filtration to obtain wet STG base form base I (low crystallinity). The sample was dried at 50° C. overnight to obtain STG base crystalline form base I.
- A sample of STG base (100 mg) was dissolved in dioxane (0.2 ml) at 55° C. for 2 hours, then cooled to 25° C., and stirred at 25° C. overnight. The product was isolated by vacuum filtration to obtain wet STG base form base I. The sample was dried at 50° C. overnight to obtain STG base crystalline form base I.
- A sample of STG base (100 mg) was slurried in trifluorotoluene (0.5 ml) at 70° C. for 2 hours, and then cooled to 25° C., and stirred at 25° C. overnight. The product was isolated by vacuum filtration to obtain wet STG base form base I.
- A sample of wet STG base (1 g) was dissolved in cyclopentyl methyl ether (20 ml) at 90° C. The solution was cooled to room temperature, then cooled with an ice bath, and stirred overnight. The product was isolated by vacuum filtration and dried at 50° C. in a vacuum oven (10-25 mbar) for 24 hours to obtain STG base form I (850 mg).
- A sample of wet STG base (1 g) was dissolved in isopropanol (IPA) (8 ml) at 80° C. The solution was cooled to room temperature and stirred overnight. The product was isolated by vacuum filtration, and dried at 50° C. in a vacuum oven (10-25 mbar) for 24 hours to obtain STG base form I (540 mg).
- A sample of wet STG base (1 g) was dissolved in 1-Propanol (9 ml) at 80° C. The solution was cooled to room temperature, and stirred overnight. The product was isolated by vacuum filtration, and dried at 50° C. in a vacuum oven (10-25 mbar) for 24 hours to obtain STG base form I (200 mg).
- A sample of wet STG base (1 g) was dissolved in isopropyl acetate (12 ml) at 80° C. The solution was cooled to room temperature, then cooled with an ice bath, and stirred overnight. The product was isolated by vacuum filtration, and dried at 50° C. in a vacuum oven (10-25 mbar) for 24 hours to obtain STG base form I (400 mg).
- STG base (2.50 g) was slurried in Ethyl acetate: n-hexane 1:3 (75 ml) at reflux for 55 minutes. Then cooled to room temperature and stirred at room temperature for over night.
- The product was isolated by vacuum filtration. The sample was dried at 40° C. over night to obtain a STG base crystalline form base I.
- To 30 ml of degassed trifluoroethanol (TFE) were added Ruthenium(II) chloride 1,5-cyclooctadiene complex (18.2 mg, 0.037 mmol) and (R)-(−)-1-[(S)-2-Diphenylphosphino)ferrocenyl]ethyl di-tert-butylphosphine (44.8 mg, 0.083 mmol). The solution was degassed again, and left to stir at room temperature for 1 hour. To 250 ml glass reactor were added (Z)-3-amino-1-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)but-2-en-1-one (30 g, 74.07 mmol) and 100 ml TFE. The slurry was stirred and washed three times with N2. Than, the catalyst solution was added and the mixture washed three times with N2, then switched to H2 and washed three times. The H2 pressure was set to constant pressure of 5 bar and the reaction was heated to 55° C. for 23 hours. The TFE solution (93.3% purity and 77% R) was evaporated to yield oily-STG-base.
- The solution of STG base (ca. 6 g) was concentrated until the percentage of trifluoroethanol was 39%. This solution was dissolved in methyl t-butyl ether (30 ml) at room temperature and stirred at room temperature overnight. The product was isolated by vacuum filtration. The sample was dried at 40° C. over night to obtain a STG base crystalline form base I.
Claims (36)
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US12/313,975 US20090221595A1 (en) | 2007-11-26 | 2008-11-25 | Crystalline form of sitagliptin |
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US438307P | 2007-11-26 | 2007-11-26 | |
US13487808P | 2008-07-14 | 2008-07-14 | |
US13500508P | 2008-07-15 | 2008-07-15 | |
US12/313,975 US20090221595A1 (en) | 2007-11-26 | 2008-11-25 | Crystalline form of sitagliptin |
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US12/313,975 Abandoned US20090221595A1 (en) | 2007-11-26 | 2008-11-25 | Crystalline form of sitagliptin |
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WO (1) | WO2009070314A2 (en) |
Cited By (3)
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US20100285541A1 (en) * | 2009-02-26 | 2010-11-11 | Codexis, Inc. | Transaminase biocatalysts |
US8921079B2 (en) | 2009-06-22 | 2014-12-30 | Codexis, Inc. | Transaminase reactions |
US8932836B2 (en) | 2010-08-16 | 2015-01-13 | Codexis, Inc. | Biocatalysts and methods for the synthesis of (1R,2R)-2-(3,4-dimethoxyphenethoxy)cyclohexanamine |
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US8329696B2 (en) | 2009-03-30 | 2012-12-11 | Teva Pharmaceuticals Industries Ltd. | Solid state forms of sitagliptin salts |
WO2011107494A1 (en) | 2010-03-03 | 2011-09-09 | Sanofi | Novel aromatic glycoside derivatives, medicaments containing said compounds, and the use thereof |
EP2547682A1 (en) | 2010-03-31 | 2013-01-23 | Teva Pharmaceutical Industries Ltd. | Solid state forms of sitagliptin salts |
US8530413B2 (en) | 2010-06-21 | 2013-09-10 | Sanofi | Heterocyclically substituted methoxyphenyl derivatives with an oxo group, processes for preparation thereof and use thereof as medicaments |
TW201221505A (en) | 2010-07-05 | 2012-06-01 | Sanofi Sa | Aryloxyalkylene-substituted hydroxyphenylhexynoic acids, process for preparation thereof and use thereof as a medicament |
TW201215388A (en) | 2010-07-05 | 2012-04-16 | Sanofi Sa | (2-aryloxyacetylamino)phenylpropionic acid derivatives, processes for preparation thereof and use thereof as medicaments |
TW201215387A (en) | 2010-07-05 | 2012-04-16 | Sanofi Aventis | Spirocyclically substituted 1,3-propane dioxide derivatives, processes for preparation thereof and use thereof as a medicament |
EP2691083B1 (en) | 2011-03-29 | 2017-08-02 | KRKA, tovarna zdravil, d.d., Novo mesto | Pharmaceutical composition of sitagliptin |
SI2736909T1 (en) | 2011-07-27 | 2017-08-31 | Farma Grs, D.O.O. | Process for the preparation of sitagliptin and its pharmaceutically acceptable salts |
WO2013037390A1 (en) | 2011-09-12 | 2013-03-21 | Sanofi | 6-(4-hydroxy-phenyl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
WO2013045413A1 (en) | 2011-09-27 | 2013-04-04 | Sanofi | 6-(4-hydroxy-phenyl)-3-alkyl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
EP2911655A1 (en) | 2012-10-24 | 2015-09-02 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Tpl2 kinase inhibitors for preventing or treating diabetes and for promoting -cell survival |
WO2015114657A2 (en) * | 2014-01-21 | 2015-08-06 | Cadila Healthcare Limited | Amorphous form of sitagliptin free base |
WO2016151018A1 (en) | 2015-03-24 | 2016-09-29 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Method and pharmaceutical composition for use in the treatment of diabetes |
WO2017006335A1 (en) * | 2015-07-03 | 2017-01-12 | Harman Finochem Limited | A process for preparing 7-[(3r)-3-amino-1-oxo-4-(2,4,5trifluorophenyl)butyl]- 5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazine phosphate monohydrate and its novel crystalline form h |
KR20200021774A (en) * | 2018-08-21 | 2020-03-02 | 대화제약 주식회사 | Methods of manufacturing formulations comprising sitagliptin immediate release layer, and the formulations manufactured by the methods, methods of sitagliptin immediate release layer coating, and compositions for sitagliptin immediate release layer coating |
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US7326708B2 (en) * | 2003-06-24 | 2008-02-05 | Merck & Co., Inc. | Phosphoric acid salt of a dipeptidyl peptidase-IV inhibitor |
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WO2004085661A2 (en) * | 2003-03-24 | 2004-10-07 | Merck & Co., Inc | Process to chiral beta-amino acid derivatives |
EP1667524A4 (en) * | 2003-09-23 | 2009-01-14 | Merck & Co Inc | Novel crystalline form of a phosphoric acid salt of a dipeptidyl peptidase-iv inhibitor |
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2008
- 2008-11-25 US US12/313,975 patent/US20090221595A1/en not_active Abandoned
- 2008-11-25 WO PCT/US2008/013174 patent/WO2009070314A2/en active Application Filing
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US7326708B2 (en) * | 2003-06-24 | 2008-02-05 | Merck & Co., Inc. | Phosphoric acid salt of a dipeptidyl peptidase-IV inhibitor |
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US9353355B2 (en) | 2009-02-26 | 2016-05-31 | Codexis, Inc. | Transaminase biocatalysts |
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US11078505B2 (en) | 2009-02-26 | 2021-08-03 | Codexis, Inc. | Transaminase biocatalysts |
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US8293507B2 (en) | 2009-02-26 | 2012-10-23 | Codexis, Inc. | Transaminase biocatalysts |
US20100285541A1 (en) * | 2009-02-26 | 2010-11-11 | Codexis, Inc. | Transaminase biocatalysts |
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US10138503B2 (en) | 2009-06-22 | 2018-11-27 | Codexis, Inc. | Transaminase reactions |
US9434968B2 (en) | 2009-06-22 | 2016-09-06 | Codexis, Inc. | Transaminase reactions |
US10767202B2 (en) | 2009-06-22 | 2020-09-08 | Codexis, Inc. | Transaminase reactions |
US8921079B2 (en) | 2009-06-22 | 2014-12-30 | Codexis, Inc. | Transaminase reactions |
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US8932836B2 (en) | 2010-08-16 | 2015-01-13 | Codexis, Inc. | Biocatalysts and methods for the synthesis of (1R,2R)-2-(3,4-dimethoxyphenethoxy)cyclohexanamine |
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WO2009070314A3 (en) | 2009-09-24 |
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